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Published on: February 17, 2016
Azithromycin Protects Oligodendrocyte Progenitor Cells against Lipopolysaccharide-Activated Microglia-Induced Damage
Sumana Ramarao1, Yi Pang1, Kathleen Carter1
1Division of Newborn Medicine, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Abstract:
Oligodendrocyte progenitor cells (OPC) are the primary cellular targets of brain white matter injury (WMI) in very low-birth weight (VLBW) infants. Microglia plays a significant role in inflammation-induced WMI. Our previous study showed that lipopolysaccharide (LPS)-induced OPC damage is mediated by activated microglia in vitro. We hypothesized that azithromycin (AZ) could protect OPCs against LPS-induced cytotoxicity by blocking microglial activation. Highly enriched primary rat microglia and OPCs were treated with LPS. There were 4 groups: control, LPS + Veh, AZ, and LPS + AZ. Microglia conditioned medium (MCM) was used to determine inflammatory cytokines by enzyme-linked immunosorbent assay or subsequent treatment of OPCs. We found that AZ significantly suppressed TNF-α, IL-1β, and IL-6 in LPS+Veh-treated-microglial MCM and blocked microglial nuclear factor-κB p65 nuclear translocation. AZ prevented LPS-MCM-induced OPC death and improved OPC survival as measured by activated caspase-3 immunostaining and XTT assay, respectively. AZ ameliorated LPS-MCM-induced differentiation arrest and myelin basic protein deficit in oligodendrocytes. Our data suggest that AZ is a potent inhibitor for microglia activation and may hold the therapeutic potential for WMI in VLBW infants.
Insights
Azithromycin (AZ) protects oligodendrocyte progenitor cells (OPCs) from damage caused by activated microglia. This suggests AZ may be a potential therapy for brain white matter injury (WMI) in premature infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Oligodendrocyte progenitor cells (OPCs) are vulnerable to brain white matter injury (WMI) in very low-birth weight (VLBW) infants.
- Microglia activation contributes significantly to inflammation-induced WMI.
Purpose of the Study:
- To investigate if azithromycin (AZ) can protect OPCs from lipopolysaccharide (LPS)-induced cytotoxicity by inhibiting microglial activation.
- To evaluate AZ's effects on inflammatory markers and OPC survival and differentiation.
Main Methods:
- Primary rat microglia and OPCs were co-cultured and treated with LPS and/or AZ.
- Enzyme-linked immunosorbent assay (ELISA) measured inflammatory cytokines in microglia-conditioned medium (MCM).
- OPC survival, caspase-3 activation, and oligodendrocyte differentiation were assessed.
Main Results:
- AZ significantly reduced TNF-α, IL-1β, and IL-6 levels in LPS-treated microglia.
- AZ inhibited nuclear factor-κB p65 translocation in microglia.
- AZ treatment prevented LPS-MCM-induced OPC death, improved OPC survival, and ameliorated differentiation deficits.
Conclusions:
- Azithromycin effectively inhibits microglia activation in response to LPS.
- AZ demonstrates therapeutic potential for protecting against white matter injury in VLBW infants.
